The preparation of organic compounds of high optical purity is becoming an increasingly important objective. To this end, numerous examples of methods involving chiral catalysts (both natural and unnatural) and covalently-bonded chiral auxiliaries can be cited. See for example, Noyori, R., Asymmetric Catalysis in Organic Synthesis; (John Wiley & Sons, Inc., New York) 1994; and Wong, C.-H., Whitesides, G. M., Enzymes in Synthetic Organic Chemistry; Tetrahedron Organic Chemistry Series, (Pergamon Press, Tarrytown, N.Y.) 1994; Vol. 12. Although often highly stereoselective, these methods typically embrace a single event in which bond-forming or bond-breaking takes place on a given substrate. For molecules with multiple stereocenters it would be desirable to couple several distinct asymmetric transformations in a single-vessel reaction sequence.
The reaction of the titanium homoenolate derived from 3 with N-tert-Boc-phenylalaninal 6 is known to yield the homoaldol product 4a as a single isomer as shown in Scheme 1. See, for example, (a) Armstrong III, J. D.; Hartner, Jr., F. W.; DeCamp, A. E.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1992, 33, 6599; (b) DeCamp, A. E.; Kawaguchi, A. T.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1991, 32, 1867; (c) Reetz, M. R.; Karin, R.; Griebenow, N. Tetrahedron Lett. 1994, 35, 1969; (d) Reetz, T. R.; Fox, D.N.A.; Tetrahedron Lett. 1993, 34, 1119; (e) Reetz, M. R. Angew. Chem. Int. Ed. Engl. 1991, 30, 1531; and (f) Kano, S.; Yokomatsu, T.; Shibuya, S. Tetrahedron Lett. 1991, 32, 233. The overall conversion of 1 to 4a by the known route requires four individual steps, including two stereodefining steps. The known route could likewise be used to produce 5a from 2. ##STR1##
Streamlining of the overall transformation of 1 to 4a would be desirable for improved time and cost efficiency. The success of such a process would require two distinct asymmetric transformations, an asymmetric homologation and an asymmetric homoaldol. The present invention addresses this problem by providing just such a tandem asymmetric process, which couples a 1,2-migration with a homoaldol reaction in a single-vessel reaction sequence. The process and intermediates described herein can be used in a wide variety of synthetic applications, and particularly this process can be used to make HIV protease inhibitors and endothelian antagonists.